tbuckley/cabot-search huggingface dataset:
Abstract 3410: AVATASCAN®, a pioneer of functional precision medicine in guiding clinical decision-making
Authors: Nam-Gu Her, Gi Ju Lee, Seung Yoon Hyun, San Ha Park, Jae Woo Ahn, Ji Soo Kang, Hong Boon Toh, Do-Hyun Nam
Journal: Cancer Research (2023)

Abstract Precision medicine refers to the tailoring of individual therapeutics based on each patient’s genetic, phenotypic, and clinical characteristics, therefore seeking the most effective treatment for the patient. With recent advances in genome sequencing technology, it was anticipated that identifying specific genetic alterations would contribute greatly to the realization of precision medicine. However, most cancer patients do not benefit from genomic precision medicine, as shown in recent Next Generation Sequencing (NGS)-driven clinical trials. Functional precision medicine directly uses patient tumor cells to test their ex vivo responses to diverse drugs to predict the most effective drugs. Functional precision medicine is emerging because it provides immediate translatable information to select drugs among clinically available therapeutics. AVATASCAN®, developed by Samsung Medical Center and AimedBio Inc., is a robust and accurate high throughput functional precision medicine platform with more than 1,500 historical sample data. AVATASCAN® has tested more than 1,500 cancer patient samples across 14 different tumor types, including glioblastoma, lung, colorectal, stomach and breast cancers. We achieved a tissue culture success rate and a drug screening success rate of more than 90% in most tumor types. A retrospective analysis of the clinical outcomes of patients given matched drugs demonstrated actual complete/partial response in 85% of AVATASCAN® screening responders. Recognizing its potential for clinical application, AVATASCAN® was selected as one of the datasets referenced by the pediatric tumor board at Seoul National University Hospital for clinical decision-making. Furthermore, AVATASCAN® is now available in Singapore and Thailand as an early-access, premium precision medicine service. Overall, we present compelling evidence that AVATASCAN® is a valuable platform for personalized cancer therapy. Therefore, we are moving forward to adopt and expand this platform in clinical applications. Citation Format: Nam-Gu Her, Gi Ju Lee, Seung Yoon Hyun, San Ha Park, Jae Woo Ahn, Ji Soo Kang, Hong Boon Toh, Do-Hyun Nam. AVATASCAN®, a pioneer of functional precision medicine in guiding clinical decision-making [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3410.
Predicting patient decompensation from continuous physiologic monitoring in the emergency department
Authors: Sameer Sundrani, Julie Chen, Boyang Tom Jin, Zahra Shakeri Hossein Abad, Pranav Rajpurkar, David Kim
Journal: npj Digital Medicine (2023)

Anticipation of clinical decompensation is essential for effective emergency and critical care. In this study, we develop a multimodal machine learning approach to predict the onset of new vital sign abnormalities (tachycardia, hypotension, hypoxia) in ED patients with normal initial vital signs. Our method combines standard triage data (vital signs, demographics, chief complaint) with features derived from a brief period of continuous physiologic monitoring, extracted via both conventional signal processing and transformer-based deep learning on ECG and PPG waveforms. We study 19,847 adult ED visits, divided into training (75%), validation (12.5%), and a chronologically sequential held-out test set (12.5%). The best-performing models use a combination of engineered and transformer-derived features, predicting in a 90-minute window new tachycardia with AUROC of 0.836 (95% CI, 0.800-0.870), new hypotension with AUROC 0.802 (95% CI, 0.747-0.856), and new hypoxia with AUROC 0.713 (95% CI, 0.680-0.745), in all cases significantly outperforming models using only standard triage data. Salient features include vital sign trends, PPG perfusion index, and ECG waveforms. This approach could improve the triage of apparently stable patients and be applied continuously for the prediction of near-term clinical deterioration.
Abstract 3789: Circular RNA expression is enriched in breast cancer extracellular vesicles and is associated with chemotherapy resistance
Authors: Harrison Ngue, Jitendra Shrestha, Hyejin Kim, Shobha Vasudevan
Journal: Cancer Research (2023)

Abstract Up to 90% of failures in chemotherapy treatment are associated with metastatic-related drug resistance. Extracellular vesicles (EVs) are believed to play a role in the spread of chemotherapy resistance through the horizontal transfer of oncoproteins and noncoding RNA species, but the underlying mechanisms for this are not fully understood. Here, we study EV biogenesis, release, and uptake in the context of breast cancer chemoresistance. Specifically, we characterized the bioactive cargoes in EVs secreted by chemoresistant triple negative breast cancer cells and chemoresistant estrogen receptor-positive breast cancer cell lines. Preliminary data show that these EVs contain unusually high levels of circular RNAs, small RNA species formed covalently through backsplicing and are typically noncoding. When chemosensitive cells absorb these circRNA-enriched EVs, they experience a significant increase in resistance phenotypes. Moreover, knockdown of the circRNAs via antisense oligonucleotides results in decreased chemoresistance, suggesting a role of circRNAs in the development of chemotherapy resistance. Previous studies have shown that tumor-derived exosomal circRNAs may confer resistance by sponging microRNAs. We are exploring what the circRNAs do mechanistically to promote tumor survival, and clarifying these mechanisms as a whole will serve to potentially provide therapeutic targets against chemotherapy resistance and cancer recurrence. Citation Format: Harrison Ngue, Jitendra Shrestha, Hyejin Kim, Shobha Vasudevan. Circular RNA expression is enriched in breast cancer extracellular vesicles and is associated with chemotherapy resistance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3789.
Abstract 2279: Tumor treating fields induce immune modulation in non-small cell lung cancer
Authors: Suhe Wang, James R. Baker, Jesse Chen, Zhengyi Cao, Jayme Cannon
Journal: Cancer Research (2023)

Abstract Non-small cell lung cancer (NSCLC) is one of most common lung cancers in the general population. KRAS mutations occur in 15-30% of NSCLC. The mutation results in continuous activation of KRAS, triggering multiple kinase signaling pathways. The oncogenic features of KRAS mutations are in line with clinical observations that NSCLC patients with KRAS mutations have a worse prognosis with less benefit from chemotherapies. Although the targeted inhibition of KRAS G12C mutation in NSCLC has achieved remarkable success, the inhibition of KRAS G12D has not yet been successful. It has been reported that KRAS mutations can facilitate the development of immunosuppressive properties of the tumor microenvironment. Specifically, KRAS mutations can up-regulate regulatory T cell (Treg) population. Tumor Treating Fields (TTFields) are a cancer therapy based on noninvasive delivery of electric fields. Our current in vitro study was performed in peripheral blood mononuclear cells (PBMC) from a transgenic mouse lung cancer model with a KRAS G12D mutation. Our data showed that TTFields treatment decreased CD4+CD25+ Foxp3+ T cells intensity prepared from PBMC compared to untreated cells by flow cytometric determination. In addition, CD4+ T cells prepared from TTFields treated PBMC have enhanced IFN-γ expression levels compared to untreated PBMC. These results suggest TTFields treatment appear to correct the immunosuppressive properties created by KRAS mutations. Therefore, in vivo treatment for the inducible lung cancer with KRAS activating mutations is needed to confirm the in vitro results. In conclusion, TTFields are a potential therapeutic tool for NSCLC with KRAS G12D mutation. Citation Format: Suhe Wang, James R. Baker, Jesse Chen, Zhengyi Cao, Jayme Cannon. Tumor treating fields induce immune modulation in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2279.
Abstract 6773: Spatial dynamics of cytotoxic T lymphocyte exhaustion in reactive and tumoral tissue
Authors: Maxim De Schepper, Asier Antoranz, Nikolina Dubroja, Giuseppe Floris, Frederik De Smet, Francesca Bosisio
Journal: Cancer Research (2023)

Abstract Background The study of cytotoxic T-lymphocytes (Tcy) has shown increased attention from the scientific community in the last years because of their predictive role in anti-cancer therapy with specific interest in immune check point blocking therapy. However, most of these studies have used bulk or dissociation-based single-cell technologies to draw their biological insights. Lately, new spatial -omics technologies are increasing our knowledge on this population by adding the spatial location of these cells in-situ in the native structure of the tissue. In this study, we have compared the activation of Tcy in reactive and cancerous conditions at single cell level and in the micro-anatomical context of the tissue. Experimental procedures One tissue micro array slide containing: reactive tonsil, inflammatory liver disease, breast cancer, glioblastoma and melanoma was stained using the COMET™ instrument (Lunaphore Technologies SA) for a multiplex panel of 20 markers. The derived multiplexed images were analyzed using the DISSCOVERY software platform developed by the MILAN Unit at KU Leuven (Belgium). 12/20 markers were specifically aimed at identifying the main cell populations in the tissue (CD11b, CD163, CD20, CD3, CD31, CD4, CD56, CD68, CD8, CK, FOXP3, S100) while the remaining 8 markers were aimed at adding functional information on immune cell types of interest (CD69, HLA-DR, Ki67, LAG3, OX40, PD-1, PD-L1, TIM3). Results The general activation levels of the Tcy in the reactive conditions were higher than in the three cancer subtypes. When looking at Tcy activation as a function of the distance from the vascular structures (identified via CD31+ endothelial cells), we observed an orderly distribution of activated Tcy around CD31+ endothelial cells with a gradient of increasing exhaustion levels with increasing distance from the vessel in the reactive conditions. In the cancer samples, on the contrary, a patchy disorderly organized pattern of exhausted and activated Tcy was observed around the vessels. Conclusion The spatial location of inflammatory cells plays a critical role to understand their functional behavior and thanks to technological progress it is now possible to start doing this at scale. The study of the dynamics of exhaustion of Tcy in the tissue will help clarify the interplay between cancer cells and immune environment. These results will be crucial to better select patients who may benefit the most of immune check point blockade. Citation Format: Maxim De Schepper, Asier Antoranz, Nikolina Dubroja, Giuseppe Floris, Frederik De Smet, Francesca Bosisio. Spatial dynamics of cytotoxic T lymphocyte exhaustion in reactive and tumoral tissue. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6773.
Abstract 362: Development of PEP3-IR750 probe to identify adipose tissue and cachexia in murine models
Authors: Sophia Chakrabarty, Zheng Han, Lacey R. McNally
Journal: Cancer Research (2023)

Abstract Background Cachexia is a multifactorial adipose and muscle wasting disease that is frequently identified in patients with cancer. Cachexia results from increased lipolysis, proteolysis, inflammation, and tumor/host secreted cytokines. Unfortunatly, cachexia is often identified in the clinic at late stages after substantial adipose and muscle loss has occured. Currently, the identification of cachexia in its adipose-wasting stages is difficult due to the lack of a diagnostic imaging tool that easily, objectively, and reproducibly monitors the loss of adipose tissue. Objective identification of fat stores could be used for the early identification and monitoring of cachexia. Methods We used Fmoc chemistry to synthesize a peptide that binds to fat, i.e. PEP3, CPATAEPC, and scrambled control peptide, AQYLNPS. Following microwave peptide synthesis, we lyophilized, purified, and conjugated the peptides to the Hilyte Fluor750 succinimidyl ester using NHS reaction. Excess dye was removed using dialysis in water. IR750-PEP3 probe was assessed using HPLC and spectroscopy to determine the probe concentrations. Sixty nanomoles of probe reconstituted in 200 µL PBS (pH 7.4). Ex vivo interscapular, perirenal, and omental fat and control muscle tissues were incubated with 20 µM IR750-PEP3 and scrambled probes for 1 h in a 6-well plate, tissues washed with PBS to remove unbound probe, and imaged using near infrared fluorescence. In vivo testing assessed, 60 nmol intravenous injection into healthy female mice. Mice were imaged using MSOT 4 h post injection, images were reconstructed and spectrally unmixed based upon the spectrums of brown fat and IR750 dye. Parametric maps were generated via MATLAB to identify distributions of fat and injected probes. Secondary confirmation of probe biodistribution was conducted using NIR fluorescence of excised tissues. Results Following injecting 60 nmol of IR750-PEP3, MSOT images confirmed that the PEP3-IR750 dye localized to areas of fat in the interscapular, and perirenal areas in vivo compared to scrambled control (p=0.05, Mann-Whitney U Test). The higher capability of PEP3-IR750 to localize to fat tissue was further confirmed by ex vivo evaluation of PEP3-IR750 and scramble probes-IR750 (p=0.05, Mann-Whitney U Test). Notably, there was a complete lack of signal in the control muscle tissue. Conclusion PEP3-IR750 can specifically identify fat in mice, and our data supports its potential use in the early identification of cachexia. Citation Format: Sophia Chakrabarty, Zheng Han, Lacey R. McNally. Development of PEP3-IR750 probe to identify adipose tissue and cachexia in murine models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 362.
Abstract 2373: Combination treatment with pH modulating drugs and immune checkpoint inhibitors increases TALL-104 cytotoxicity in preclinical co-culture experiments
Authors: Ryan Malpass, Kelsey E. Huntington, Thomas Brown, Lanlan Zhou, Leiqing Zhang, Arunasalam Navaraj, Wafik S. El-Deiry, Aaron Maxwell
Journal: Cancer Research (2023)

Abstract Hepatocellular carcinoma (HCC) and colorectal cancer liver metastases (CRCLM) are leading causes of death worldwide, with therapeutic options limited to surgical resection and trans-arterial chemoembolization (TACE). TACE is a minimally-invasive approach to induce cancer cell death through a local hypoxia-dependent mechanism, and intrahepatic catheterization further enables the delivery of therapeutic agents to the tumor microenvironment (TME). Phase 1 clinical trials are ongoing for treatment of primary liver cancer and uveal melanoma with liver metastases using pressure-enabled drug delivery of SD-101 in combination with systemic immune checkpoint inhibitors (ICIs). Since acidosis is associated with immunosuppression in the TME, pH modulating drugs (PMDs) may restore physiologic conditions and augment treatment response for patients undergoing TACE with immunotherapy. Pre-clinical studies using PMDs with ICIs or adoptive immune cell transfer have demonstrated increased tumor lymphocyte infiltration, increased survival, and reduced tumor volume compared to ICI treatment or T cell infusion alone. High-throughput fluorescent imaging of HCC or CRC lines co-cultured with TALL-104 cells indicates increased cancer cell death with PMD treatment alone, while imaging studies of combination PMD and ICI treatment are underway. In addition, Luminex 200 cytokine profiling of Hep3B indicates that the NHE1 inhibitor cariporide decreases HCC production of IL-8 and GDF-15 under normoxia and the proton pump inhibitor lansoprazole increases GDF-15 and MIF and decreases B2M, IL-8, CXCL10, and CXCL5. Combination PMD and ICI studies are needed to inform drug combinations and dosages in syngeneic murine models of primary liver cancer and CRCLM. Subcutaneous and orthotopic tumor models are expected to demonstrate the efficacy of local PMD treatment with systemic immunotherapy. Citation Format: Ryan Malpass, Kelsey E. Huntington, Thomas Brown, Lanlan Zhou, Leiqing Zhang, Arunasalam Navaraj, Wafik S. El-Deiry, Aaron Maxwell. Combination treatment with pH modulating drugs and immune checkpoint inhibitors increases TALL-104 cytotoxicity in preclinical co-culture experiments [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2373.
Abstract 4755: Screening non-small cell lung cancer organoids with epigenetic probes
Authors: Khadija Jafarova, Panagiotis Prinos, Nikolina Radulovich, Takamasa Koga, Cheryl Arrowsmith, Geoffrey Liu, Ming Sound Tsao
Journal: Cancer Research (2023)

Abstract Introduction: NSCLC is associated with high cancer-related mortality worldwide. Epigenetic modifications at the chromatin level have widely been linked to carcinogenesis. Epigenetic regulation not only contributes to the development of cancer, but it may also confer resistance to therapies by promoting the survival of clones that can overcome treatment-induced stress or give rise to complex tumor heterogeneity in response to cancer therapy. Investigating susceptibility resulting from epigenetic aberrations in tumor cells may reveal novel markers of therapies that target epigenetic aberrations. In this study, we treated NSCLC organoid models with a library of 41 epigenetic probes to identify epigenetic targets that affect tumor cell survival. Methods: Epigenetic screen. NSCLC organoid models were established from resected patient tumors or patient-derived xenografts. Organoids were dissociated into single cells and plated in matrigel-coated 384-well plate. Each model was treated with a library of epigenetic probes (1uM) and a DMSO control over a period of 8 days. Library was provided by Structural Genomics Consortium (www.thesgc.org) and contained compounds targeting a variety of protein domains some of which had activity on acetylation, methylation, histone de-methylation etc. CellTiter-Glo assay was performed to measure cell survival. Results: Among the epigenetic probe compounds tested on 26 models, LLY 283 (PRMT5 inhibitor) showed the most significant effect on inhibition of cell growth in 69% of organoid models (18/26) with suppression of &amp;gt;=40% as compared to the DMSO control. To assess differential responses to treatment with LLY 283, four organoid models were treated with 21 different concentrations of PRMT5 inhibitor. Growth curves of a sensitive (XDO181) and a less sensitive (XDO4056) models were compared. For XDO181 and XDO4056, IC50 values were calculated to be 4.7 nM and 31.8 nM respectively, indicating that a less sensitive model is associated with a 7-fold increase in IC50 value compared to the sensitive model. Conclusion: A screen using epigenetic compounds on NSCLC patient-derived organoids revealed sensitivity to PRMT5 inhibitor in 69% of the organoid models tested. Further investigation will explore the mechanisms that are associated with sensitivity to PRMT5 inhibition. Citation Format: Khadija Jafarova, Panagiotis Prinos, Nikolina Radulovich, Takamasa Koga, Cheryl Arrowsmith, Geoffrey Liu, Ming Sound Tsao. Screening non-small cell lung cancer organoids with epigenetic probes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4755.
Abstract 4941: Development of small molecule RPN13 inhibitors for treatment of glioblastoma
Authors: Yung-Nien Chang, Ravi K. Anchoori, Alex Shimura Yamashita, Marina da Costa Rosa
Journal: Cancer Research (2023)

Abstract Glioblastoma (GBM) is an aggressive and deadly brain cancer with a one-year median survival due to the lack of effective targeted treatments. Our goal is to develop a small molecule inhibitor targeting RPN13 protein in the 19S proteasome complex as a new drug for GBM. RPN13 is a proteasome ubiquitin receptor that recognizes ubiquitin-conjugated proteins that are thus tagged for degradation via the 20S proteasome enzymatic complex. GBM is highly sensitive to proteasome inhibition due to its aggressive growth and accumulation of misfolded polyubiquitinated proteins that is insufficiently managed despite increased proteasome levels and enhanced proteasome activity (i.e. proteotoxic stress). Up Therapeutics judiciously designed drug-like RPN13 inhibitors to overcome limitations in the prototype RPN13 inhibitor RA190 identified at Johns Hopkins University. We selected Up284 as lead compound based upon our preliminary studies showing drug-like characteristics, specificity (binding to Cys88 of RPN13), and proteasome inhibition that produces a cytotoxic accumulation of polyUb proteins, ER stress, and reactive oxygen species. Up284 treatment selectively triggers apoptosis in solid tumor types including GBM cell lines and oncospheres. A suitable Up284 formulation was selected by measuring aqueous solubility, stability and on-target activity in mice imaged using a proteasome-dependent in vivo reporter. Up284 can be administered i.v. or orally, and it penetrates through the BBB. As a proof of concept for treatment of GBM, Up284 demonstrated on-target activity in intracranial syngeneic GL261 tumor model by inhibiting proteasome function in tumor tissues. Up284 also well tolerated and regressed tumors in syngeneic, xenograft and spontaneous models of ovarian and breast cancers with acceptable safety profile. Up284 also synergize with current frontline chemotherapeutics and can be used as a single agent or in combination for the treatment of wide range of cancers. Citation Format: Yung-Nien Chang, Ravi K. Anchoori, Alex Shimura Yamashita, Marina da Costa Rosa. Development of small molecule RPN13 inhibitors for treatment of glioblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4941.